Members of the TNF (Tumor necrosis factor) ligand/TNF receptor superfamily play key roles in a large number of biological events. For instance, members of the TNF ligand/TNF receptor superfamily figure prominently in the complex interplay of positive and negative signals that regulate T cell activation, maintenance of T cell effector function, promotion of maturation of antigen-presenting cells (APCs), such as dendritic cells, and the T cell stimulation of APCs.
TNF receptors are broadly classified in three groups (Dempsey et al., 2003, “The signaling adaptors and pathways activated by TNF superfamily,” Cytokine Growth Factor Rev. 14(3-4):193-209). Receptors in the first group contain a death domain in their cytoplasmic tails. Receptors in the second group contain a TRAF interaction motif in their cytoplasmic tails. The third group of TNF receptors do not contain functional intracellular signaling domains but can act as decoy receptors.
There are nearly two dozen TNF receptors in the second group. From the standpoint of immune activation, OX40 and CD40 are of interest.
OX40 is a cell surface glycoprotein that is expressed primarily on activated CD4+ T cells and some human T cell leukemia virus type I (HTLV-I)-infected T cell lines, but is not typically expressed on resting naïve T cells, resting peripheral T cells, peripheral B cells, or thymocytes. OX40 is a costimulatory molecule that is expressed about 24 to 72 hours after activation of T cells. OX40 ligand (“OX40L”) is expressed on activated APCs but not on resting APCs. Binding of OX40L to OX40 on activated T cells prevents activated T cells from dying and subsequently increases cytokine production. As a result of enhancing survival of activated T cells, OX40 thus plays an important role in maintaining an immune response beyond the first few days and leads to a memory response.
CD40 is also a cell surface glycoprotein. CD40 is expressed on a variety of cells in the immune system, such as B cells, dendritic cells, macrophages, and monocytes. CD40 is not only expressed by normal immune cells, but also by many malignant cells.
CD40 ligand (“CD40L”) is the cognate ligand for CD40 and is expressed primarily by activated T cells. Binding of CD40L to CD40 on non-tumor cells results in proliferation of the cells. In contrast, binding of CD40L to CD40 on tumor cells often results in tumor cell apoptosis. Reviews of the CD40/CD40 ligand signaling axis are available. See, e.g., van Kooten et al., 2000, J Leukoc Biol. 67(1): 2-17.
The biological activities of the CD40/CD40L axis and, separately, the OX40/OX40L axis, have led to the suggestion of various therapeutic agents. There is a need in the art for improved therapeutics pertaining to these signaling axes.